Mechanisms of Drug Actions by Enzyme Inhibition:
Gram-positive bacteria possess a thick cell wall composed
of a cellulose-like structural sugar polymer covalently bound
to short peptide units in layers.The polysaccharide portion of
the peptidoglycan structure is made of repeating units of N-acetylglucosamine
linked b-1,4 to N-acetylmuramic acid (NAG-NAM).
The peptide varies, but begins with L-Ala and ends with D-Ala.
In the middle is a dibasic amino acid, diaminopimelate (DAP).
DAP (orange) provides a linkage to the D-Ala (gray) residue on
an adjacent peptide.
The bacterial cell wall synthesis is completed when a cross
link between two peptide chains attached to polysaccharide backbones
The cross linking is catalyzed by the enzyme transpeptidase.
First the terminal alanine from each peptide is hydrolyzed and
secondly one alanine is joined to lysine through an amide bond.
Penicillin binds at the active site of the transpeptidase
enzyme that cross-links the peptidoglycan strands. It does this
by mimicking the D-alanyl-D-alanine residues that would normally
bind to this site. Penicillin irreversibly inhibits the enzyme
transpeptidase by reacting with a serine residue in the transpeptidase.
This reaction is irreversible and so the growth of the bacterial
cell wall is inhibited.
Since mammal cells do not have the same type of cell walls,
penicillin specifically inhibits only bacterial cell wall synthesis.
Bacterial Resistance to Penicillin:
As early as the 1940s, bacteria began to combat the effectiveness
of penicillin. Penicillinases (or beta-lactamases) are enzymes
produced by structurally susceptable bacteria which renders penicillin
useless by hydrolysing the peptide bond in the beta-lactam ring
of the nucleus. Penicillinase is a response of bacterial adaptation
to its adverse environment, namely the presence of a substance
which inhibits its growth. Many other anitbiotics are also rendered
ineffective because of this same type of resistance.
Severe Allergic Shock Reactions to Penicillin:
It is estimated that between 300-500 people die each year
from penicillin-induced anaphylaxis, a severe allergic shock
reaction to penicillin. In afflicted individuals, the beta-lactam
ring binds to serum proteins, initiating an IgE-mediated inflammatory